Multiple sclerosis (MS) is a chronic immune mediated disease of the central nervous system (CNS), which is the leading cause for neurological disability in young adults. The pathological process of MS includes immune cell infiltrations, oligodendrocyte death, demyelination and axonal damage. Several pathological and imaging studies indicate that the chronic disability is attributed mainly to axonal damage. Axonal damage in MS occurs in the early phase of the disease, in actively demyelinating lesions. In later stages of the disease, however, an ongoing, low grade axonal degeneration occurs in silent inactive plaques but not in remyelinated axons.
Spontaneous remyelination is a regular feature at early stages of lesion formation in some MS cases. Nevertheless, the remyelination process eventually fails due to environmental factors and intrinsic properties of progenitor cells.
The potential of Human embryonic stem cells (hESC) [1, 2] to differentiate into oligodendroglial cells was demonstrated both with mouse and human ES cells [3-7]. Moreover, the potential of ES cells-derived neural progeny to remyelinate in genetic models of hypo/dysmyelination and in models of focal demyelination was shown [8-11].
Transplanted cells may have a therapeutic effect in CNS autoimmune disorders not only by serving as a source of cells for regeneration, but also by immunomodulation and attenuation/abolishment of the inflammatory process. Einstein et al show that rodent fetal brain-derived neural precursor cells (NPC) transplanted into the ventricles decrease brain inflammation [12]. Similarly, peripherally injected rodent brain-derived NPC migrate into white matter and decrease brain inflammation [14]. Pluchino et al. show that intravenously injected, adult rodent brain-derived NPC, promote functional recovery in a chronic model of MS (Experimental Autoimmune Encephalomyelitis, EAE) [15]. In a later publication, Pluchino et al [14] show that adult rodent brain-derived NPC promote neuroprotection using immune-like functions, e.g. induce apoptosis of encephalitogenic T cells, exerting their effect within the CNS. Einstein et al [13] show that intravenous injection of rodent-fetal-derived NPC attenuates EAE by interacting with the peripheral immune system.
Also described is a system for regulating the immune response in the context of regenerative medicine or treatment of autoimmune disease, e.g. multiple sclerosis. The inventors propose administering undifferentiated human ES cells at the site of the pathology in an attempt to inhibit an immune response. However, since one of the inherent properties of undifferentiated ES cells is to generate tumors, this approach is probably not suitable for use in vivo, and hence immune modulation by cell therapy requires a different approach [23].